This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic 08-DK-106: Genomics of complex diseases. The innate immune system is the first-line of defense against harmful bacteria and viruses. It senses foreign invaders through proteins called receptors on the surface of immune cells, which then convey this signal internally through a complex network or 'circuitry'of biochemical reactions resulting in the release of protein messengers such as cytokines, which trigger inflammation. In IBD, the innate immune system becomes uncontrollably or excessively over-activated resulting in defective adaptive immunity. This causes damage to the intestinal tract. Our aim is to investigate the complex control mechanisms that regulate the immune system needed to achieve the delicate balance between protecting against bacterial infections and minimizing excessive inflammatory tissue damage. By mapping out the internal circuitry and identifying the important molecular 'switches'or controllers that orchestrate this complicated circuit, we envisage that we can enhance the rational design of new and more specific drugs for IBD. In landmark genetic studies over the past two years, DNA variation in many genes has been found to be associated with Crohn's disease and ulcerative colitis. This project will discover the biological processes that are implicated by these genetic findings and identify new components that interact and work with these proteins. This will involve bringing together molecular biology, immunology and computational predictions to supplement and accelerate experimental investigations into IBD. PUBLIC HEALTH RELEVANCE: Building from the success of genome-wide association in IBD, we propose to use integrative genomics, using state-of-the-art text mining, expression and proteomic data, to place genetic variants associated with Crohn's disease and ulcerative colitis in biological pathways of relevance that determine susceptibility to disease. We will then experimentally identify the mechanisms by which these genes and variants influence IBD risk by studying cell lines and patient biopsy samples using functional RNAi and transcriptional analysis. Systematically revealing these molecular mechanisms will provide novel insights into disease biology, will expose genes and pathways that constitute high priority targets for therapeutic development and, more broadly, will provide a framework for future research efforts across in many disease areas.